Combined Src and ER blockade impairs human breast cancer proliferation in vitro and in vivo
Combined Src and ER blockade impairs human breast cancer proliferation in vitro and in vivo
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DOI：
10.1007/s10549-010-1024-7
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发表时间：
2011-07-01
影响因子：
3.8
通讯作者：
Slingerland, Joyce M.
中科院分区：
文献类型：
--
作者：
Chen, Yi;Alvarez, Edwin A.;Slingerland, Joyce M.
抗雌激素治疗通过增加p27来阻止易感的雌激素受体（ER）阳性乳腺癌。由于Src磷酸化p27以促进p27蛋白水解，在高达40%的ER阳性癌症中观察到的Src激活可能有助于抗雌激素抵抗。在这篇文章中，我们发现Src抑制剂saracatinib（AZD 0530）与ER阻断药物一起治疗通过p27增加乳腺癌细胞周期阻滞。Saracatinib和氟维司群一起使用比单独使用任何一种药物更有效地增加了p27，降低了Ki 67，并损害了体内MDA-MB-361异种移植肿瘤的生长。相反，saracatinib单药治疗迅速引起耐药性。由于ER和Src联合抑制延迟了体内耐药的发生，这些数据支持对saracatinib联合氟维司群治疗ER阳性乳腺癌女性进行进一步的临床研究。蛋白质组学分析显示，在saracatinib耐药肿瘤中，mTOR通路存在显著的旁路激活。在saracatinib存在下，ER阳性乳腺癌细胞系长期培养后也出现mTORC 1活化。这些数据表明了耐药肿瘤的蛋白质组学分析在鉴定耐药的潜在手段方面的实用性。mTOR激酶抑制剂与saracatinib联合使用可能会颠覆耐药性，并证明比单独使用saracatinib更有效。
Antiestrogen therapies arrest susceptible estrogen receptor (ER)-positive breast cancers by increasing p27. Since Src phosphorylates p27 to promote p27 proteolysis, Src activation observed in up to 40% of ER-positive cancers may contribute to antiestrogen resistance. In this article, we show that treatment with the Src-inhibitor saracatinib (AZD0530) together with ER-blocking drugs increased breast cancer cell cycle arrest via p27. Saracatinib and fulvestrant together more effectively increased p27, reduced Ki67, and impaired MDA-MB-361 xenograft tumor growth in vivo than either of the drugs alone. In contrast, saracatinib monotherapy rapidly gave rise to drug resistance. Since combined ER and Src inhibition delays development of resistance in vivo, these data support further clinical investigation of saracatinib in combination with fulvestrant for women with ER-positive breast cancer. Proteomic analysis revealed striking bypass activation of the mTOR pathway in saracatinib-resistant tumors. mTORC1 activation also arose following long-term culture of ER-positive breast cancer lines in the presence of saracatinib. These data indicate the utility of proteomic analysis of drug-resistant tumors to identify potential means of drug resistance. The use of mTOR kinase inhibitors with saracatinib may subvert drug resistance and prove to be more effective than saracatinib alone.